The overall goal of our research program is to gain a greater understanding of the intercellular and intracellular signaling pathways that provide neuroprotection of both rod and cone photoreceptor cells. The specific objective of this renewal application is to investigate the role of phosphoinositides (PI), particularly those produced by phosphoinositide 3-kinase (PI3K), in this process. Studies from our laboratory over the past two decades have shown that the retina and both rod and cone outer segments have an active PI metabolism. Interestingly, conditional deletion of class I PI3K from cones resulted in an age-related cone degeneration and the phenotype was not rescued by healthy rods, suggesting that rod-derived cone survival factors may signal through cone PI3K. The Aims of the proposed research are: 1) to define the relationship between the phosphoinositide signaling pathway and cone survival, 2) to search for the mechanisms of cone cell death in retinas with rod-specific mutations, and 3) find ways to rescue sick and dying cones. It is our hypothesis that PI3K-generated PIs provide neuroprotection and regulate cellular processes requisite for promoting and sustaining cone photoreceptor functionality and viability. In humans, age-related macular degeneration and diabetic retinopathy are the most common disorders affecting cones. Cones also are affected indirectly in diseases such as retinitis pigmentosa and directly in cone and cone-rod dystrophies. Achieving the above Aims will provide the basis for the development of novel therapeutic interventions to prevent the progressive and irreversible loss of cone viability, structural integrity, and function.